新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性

doi:10.7503/cjcu20130837

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (5): 981.doi: 10.7503/cjcu20130837

新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性

刘海彬¹(), 吕萍¹, 潘宁宁¹, 艾丽梅¹, 刘永祥²

1. 辽宁科技学院生物医药与化学工程学院, 本溪 117004
2. 沈阳药科大学制药工程学院, 沈阳 110016

收稿日期:2013-08-29 出版日期:2014-05-10 发布日期:2014-04-03
作者简介:联系人简介: 刘海彬, 女, 博士, 副教授, 主要从事药物合成和金属有机化学方面的研究. E-mail:haibin0616@163.com
基金资助:
辽宁省高等学校优秀人才支持计划(批准号: LJQ2011130)、国家自然科学基金(批准号: 21202103)和辽宁省教育厅科研项目(批准号: L2010204)资助

Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure^†

LIU Haibin^1,^*(), LÜ Ping¹, PAN Ningning¹, AI Limei¹, LIU Yongxiang²

1. School of Biomedical & Chemical Engineering, Liaoning Institute of Science and Technology, Benxi 117004, China
2. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China

Received:2013-08-29 Online:2014-05-10 Published:2014-04-03
Contact: LIU Haibin E-mail:haibin0616@163.com
Supported by:
† Supported by the Program for Liaoning Excellent Talents in University(No.LJQ2011130), the National Natural Science Foundation of China(No.21202103) and the Program of Liaoning Provincial Committee of Education, China(No.L2010204)

摘要/Abstract

摘要：

以4,5-二甲氧基-2-氨基苯甲酸和醋酸甲脒为原料, 经环化、氯化、胺化和缩合反应, 合成了15个新的喹唑啉哌嗪缩氨基硫脲衍生物, 其结构经¹H NMR, ¹³C NMR, HRMS及元素分析确认. 采用MTT法测试了化合物6a~6o对表皮生长因子受体(EGFR)过度表达的人乳腺癌MCF-7、人肺癌A549和人前列腺癌PC3的体外抗癌活性. 结果表明, 部分化合物表现出较强的抗癌活性, 其中, 化合物6a和6o对3种癌细胞的抗癌活性优于对照药拉帕替尼(Lapatinib), 略低于对照药阿霉素(ADM). 化合物6a和6o对MCF-7的IC₅₀值分别为6.97和6.99 μmol/L, 对A549的IC₅₀值分别为5.15和3.11 μmol/L, 而对PC3的IC₅₀值分别为2.30和1.42 μmol/L. 本文还初步探讨了化合物结构与抗癌活性之间的关系.

关键词: 表皮生长因子受体(EGFR), 喹唑啉, 缩氨基硫脲, 抗癌活性

Abstract:

To find new EGFR inhibitors, 15 novel quinazoline derivatives containing thiosemicarbazone structure were designed and synthesized from 2-amino-4,5-dimethoxybenzoic acid and formamidine acetate by the cyclization, chlorination, amination and condensation reactions. All structures of target compounds were confirmed by ¹H NMR,¹³C NMR, HRMS and elemental analysis. The in vitro anticancer activities of compounds 6a—6o against EGFR over-expressing of MCF-7(Human breast cancer), A549(Human pulmonary adenocarcinoma) and PC3(Human prostate cancer) cell lines were tested using colorimetric MTT assay. The results indicated that several compounds showed potent activity. Compounds 6a and 6o were more potent than Lapatinib, but slightly weaker than ADM against the three cell lines. The IC₅₀ values of compounds 6a and 6o against MCF-7 cell line were 6.97 and 6.99 μmol/L, against A549 were 5.15 and 3.11 μmol/L and against PC3 were 2.30 and 1.42 μmol/L, respectively. Preliminary structure-activity relationship was also discussed.

Key words: Epidermal growth factor receptor(EGFR), Quinazoline, Thiosemicarbazone, Anticancer activity

中图分类号:

O626.41

TrendMD:

刘海彬, 吕萍, 潘宁宁, 艾丽梅, 刘永祥. 新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性. 高等学校化学学报, 2014, 35(5): 981.

LIU Haibin, LÜ Ping, PAN Ningning, AI Limei, LIU Yongxiang. Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure^†. Chem. J. Chinese Universities, 2014, 35(5): 981.

图/表 4

参考文献 22

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Compound	R₁	R₂	Compound	R₁	R₂
6a	H	2-Pyridyl	6i	H	2-Nitrophenyl
6b	H	3-Pyridyl	6j	H	2-Fluorophenyl
6c	H	4-Pyridyl	6k	CH₃	4-Methoxyphenyl
6d	CH₃	3-Pyridyl	6l	Phenyl	Phenyl
6e	CH₃	4-Pyridyl	6m	CH₃	2-Furyl
6f	H	4-Fluorophenyl	6n	CH₃	2-Thienyl
6g	H	4-Methoxyphenyl	6o	CH₃	2-Thiazolyl
6h	H	4-Nitrophenyl

Compound	R₁	R₂	Compound	R₁	R₂
6a	H	2-Pyridyl	6i	H	2-Nitrophenyl
6b	H	3-Pyridyl	6j	H	2-Fluorophenyl
6c	H	4-Pyridyl	6k	CH₃	4-Methoxyphenyl
6d	CH₃	3-Pyridyl	6l	Phenyl	Phenyl
6e	CH₃	4-Pyridyl	6m	CH₃	2-Furyl
6f	H	4-Fluorophenyl	6n	CH₃	2-Thienyl
6g	H	4-Methoxyphenyl	6o	CH₃	2-Thiazolyl
6h	H	4-Nitrophenyl

Compound	R₁	R₂	IC₅₀/(μmol·L^-1)
Compound	R₁	R₂	MCF-7	A549	PC3
6a	H	2-Pyridyl	6.97±1.03	5.15±2.15	2.30±1.34
6b	H	3-Pyridyl	80.79±2.12	120.76±1.16	148.69±1.89
6c	H	4-Pyridyl	>150	>150	>150
6d	CH₃	3-Pyridyl	24.07±1.55	20.48±1.79	16.37±2.12
6e	CH₃	4-Pyridyl	>150	>150	>150
6f	H	4-Fluorophenyl	26.70±2.21	35.01±1.58	28.50±1.69
6g	H	4-Methoxyphenyl	>150	>150	>150
6h	H	4-Nitrophenyl	>150	>150	>150
6i	H	2-Nitrophenyl	60.97±1.36	4.74±1.18	>150
6j	H	2-Fluorophenyl	>150	5.30±2.02	>150
6k	CH₃	4-Methoxyphenyl	>150	>150	>150
6l	Phenyl	Phenyl	32.16±2.45	17.82±2.73	92.75±1.59
6m	CH₃	2-Furyl	>150	115.66±1.66	>150
6n	CH₃	2-Thienyl	29.49±2.42	28.68±1.67	24.93±1.93
6o	CH₃	2-Thiazolyl	6.99±1.77	3.11±2.58	1.42±1.82
ADM			0.97±2.63	0.86±1.52	0.74±1.85
Lapatinib			32.16±1.34	11.88±1.95	15.40±2.04

Compound	R₁	R₂	IC₅₀/(μmol·L^-1)
Compound	R₁	R₂	MCF-7	A549	PC3
6a	H	2-Pyridyl	6.97±1.03	5.15±2.15	2.30±1.34
6b	H	3-Pyridyl	80.79±2.12	120.76±1.16	148.69±1.89
6c	H	4-Pyridyl	>150	>150	>150
6d	CH₃	3-Pyridyl	24.07±1.55	20.48±1.79	16.37±2.12
6e	CH₃	4-Pyridyl	>150	>150	>150
6f	H	4-Fluorophenyl	26.70±2.21	35.01±1.58	28.50±1.69
6g	H	4-Methoxyphenyl	>150	>150	>150
6h	H	4-Nitrophenyl	>150	>150	>150
6i	H	2-Nitrophenyl	60.97±1.36	4.74±1.18	>150
6j	H	2-Fluorophenyl	>150	5.30±2.02	>150
6k	CH₃	4-Methoxyphenyl	>150	>150	>150
6l	Phenyl	Phenyl	32.16±2.45	17.82±2.73	92.75±1.59
6m	CH₃	2-Furyl	>150	115.66±1.66	>150
6n	CH₃	2-Thienyl	29.49±2.42	28.68±1.67	24.93±1.93
6o	CH₃	2-Thiazolyl	6.99±1.77	3.11±2.58	1.42±1.82
ADM			0.97±2.63	0.86±1.52	0.74±1.85
Lapatinib			32.16±1.34	11.88±1.95	15.40±2.04

新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性

Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure^†

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新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性

Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure†

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Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure^†